Despite recent progress in the treatment of advanced stage pancreatic ductal adenocarcinoma (PDAC) through the use of toxic combination chemotherapy, the median survival remains under one year. Further therapeutic advances for this deadly disease will likely require a detailed understanding of the underlying pathophysiologic mechanisms driving this cancer and how these pathways can be specifically targeted. One such mechanism is the reliance of pancreatic ductal adenocarcinoma (PDAC) cells on aerobic glycolytic metabolism, broadly known as the Warburg effect. Although this key metabolic adaptation has been exploited diagnostically for decades (PET scan), little is known about how this process is regulated in pancreatic tumors. In recent studies, our laboratory showed that the histone deacetylase SIRT6 functions as a central regulator of glycolytic metabolism and is downregulated in human PDAC cancers. Strikingly, our preliminary data shows that loss of SIRT6 dramatically accelerates the development of PDAC in genetically engineered mouse models (GEMMs), leading to metastatic disease, a phenotype rarely observed in these models of PDAC. Further, restoration of SIRT6 expression in established PDAC cells reduces both aerobic glycolysis and proliferative capacity. In the experiments outlined in this proposal, we will address: 1-how SIRT6 may use its histone deacetylase activity to regulate glycolysis and 2- test whether pathways rendered hyperactive in SIRT6-deficient PDAC tumors may be therapeutically targeted. Thus, the proposed studies will allow us to understand the fundamental metabolic alterations mediated by SIRT6 in PDAC cells and whether SIRT6-deficient tumors may represent a molecularly-defined subset of PDAC that is sensitive to therapeutic inhibitors of glycolysis.